Institute for Clinical Pharmacodynamics, Latham, New York, USA.
Antimicrob Agents Chemother. 2012 Jan;56(1):130-6. doi: 10.1128/AAC.00277-10. Epub 2011 Oct 3.
Exposure-response analyses for efficacy and safety were performed for tigecycline-treated patients suffering from community-acquired pneumonia. Data were collected from two randomized, controlled clinical trials in which patients were administered a 100-mg loading dose followed by 50 mg of tigecycline every 12 h. A categorical endpoint, success or failure, 7 to 23 days after the end of therapy (test of cure) and a continuous endpoint, time to fever resolution, were evaluated for exposure-response analyses for efficacy. Nausea/vomiting, diarrhea, headache, and changes in blood urea nitrogen concentration (BUN) and total bilirubin were evaluated for exposure-response analyses for safety. For efficacy, ratios of the free-drug area under the concentration-time curve at 24 h to the MIC of the pathogen (fAUC(0-24):MIC) of ≥12.8 were associated with a faster time to fever resolution; patients with lower drug exposures had a slower time to fever resolution (P = 0.05). For safety, a multivariable logistic regression model demonstrated that a tigecycline AUC above a threshold of 6.87 mg · hr/liter (P = 0.004) and female sex were predictive of the occurrence of nausea and/or vomiting (P = 0.004). Although statistically significant, the linear relationship between tigecycline exposure and maximum change from baseline in total bilirubin is unlikely to be clinically significant.
对患有社区获得性肺炎的接受替加环素治疗的患者进行了疗效和安全性的暴露-反应分析。数据来自两项随机对照临床试验，患者接受了 100mg 的负荷剂量，然后每 12 小时给予 50mg 的替加环素。在疗效的暴露-反应分析中，评估了治疗结束后 7 至 23 天（治愈测试）的成功或失败的分类终点和发热消退时间的连续终点。对恶心/呕吐、腹泻、头痛以及血尿素氮浓度（BUN）和总胆红素的变化进行了安全性的暴露-反应分析。对于疗效，24 小时时游离药物浓度-时间曲线下面积与病原体 MIC 的比值（fAUC(0-24):MIC）≥12.8 与发热消退时间更快相关；药物暴露较低的患者发热消退时间较慢（P=0.05）。对于安全性，多变量逻辑回归模型表明，替加环素 AUC 超过 6.87mg·hr/liter 的阈值（P=0.004）和女性是恶心和/或呕吐发生的预测因素（P=0.004）。虽然具有统计学意义，但替加环素暴露与总胆红素从基线的最大变化之间的线性关系不太可能具有临床意义。
